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Functions of transforming growth factor-beta family type I receptors and Smad proteins in the hypertrophic maturation and osteoblastic differentiation of chondrocytes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
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2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 37, 33545-33558 p.Article in journal (Refereed) Published
Abstract [en]

We investigated the effects of bone morphogenetic protein (BMP)-2, a member of the transforming growth factor-beta superfamily, on the regulation of the chondrocyte phenotype, and we identified signaling molecules involved in this regulation. BMP-2 triggers three concomitant responses in mouse primary chondrocytes and chondrocytic MC615 cells. First, BMP-2 stimulates expression or synthesis of type II collagen. Second, BMP-2 induces expression of molecular markers characteristic of pre- and hypertrophic chondrocytes, such as Indian hedgehog, parathyroid hormone/parathyroid hormone-related peptide receptor, type X collagen, and alkaline phosphatase. Third, BMP-2 induces osteocalcin expression, a specific trait of osteoblasts. Constitutively active forms of transforming growth factor-beta family type I receptors and Smad proteins were overexpressed to address their role in this process. Activin receptor-like kinase (ALK)-1, ALK-2, ALK-3, and ALK-6 were able to reproduce the hypertrophic maturation of chondrocytes induced by BMP-2. In addition, ALK-2 mimicked further the osteoblastic differentiation of chondrocytes induced by BMP-2. In the presence of BMP-2, Smad1, Smad5, and Smad8 potentiated the hypertrophic maturation of chondrocytes, but failed to induce osteocalcin expression. Smad6 and Smad7 impaired chondrocytic expression and osteoblastic differentiation induced by BMP-2. Thus, our results indicate that Smad-mediated pathways are essential for the regulation of the different steps of chondrocyte and osteoblast differentiation and suggest that additional Smad-independent pathways might be activated by ALK-2.

Place, publisher, year, edition, pages
2002. Vol. 277, no 37, 33545-33558 p.
Keyword [en]
Activin Receptors; Type I/*physiology, Animals, Bone Morphogenetic Proteins/pharmacology, Cell Differentiation, Cell Line, Chondrocytes/drug effects/*physiology, Collagen Type II/genetics, DNA-Binding Proteins/*physiology, Humans, Hypertrophy, Mice, Osteoblasts/drug effects/*physiology, Proteins, Receptors; Transforming Growth Factor beta/*physiology, Smad Proteins, Smad1 Protein, Trans-Activators/*physiology, Transforming Growth Factor beta
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Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-10464DOI: 10.1074/jbc.M202086200PubMedID: 12082094OAI: oai:DiVA.org:uu-10464DiVA: diva2:38232
Available from: 2007-03-26 Created: 2007-03-26 Last updated: 2017-12-11Bibliographically approved

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Moustakas, Aristidis

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